Triglycerides and gallstone formation.

Changes in bile acid (BA) metabolism and gallbladder function are critical factors in the pathogenesis of gallstones. Patients with hypertriglyceridemia (HTG) - often overweight and insulin resistant - are at risk for gallstone disease. The question arises whether HTG itself contributes to gallstone formation or whether gallstone disease only associates with this disorder. Triglycerides are formed in response to fluxes of non-esterified fatty acids and glucose. Hypertriglyceridemia results from either overproduction of triglycerides by the liver, impaired lipolysis or a combination of both. Hyperinsulinemia, as observed in the insulin resistant state, stimulates very low-density lipoprotein (VLDL)-triglyceride synthesis. Peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) are the nuclear receptors involved in the regulation of lipogenesis. Microsomal triglyceride transfer protein (MTP) is involved in the production of VLDL and its activation is also under control of transcription factors as FXR and Forkhead box-O1 (FoxO1). Triglyceride and BA metabolism are linked. There is an inverse relationship between bile acid fluxes and pool size and VLDL production and SHP (small heterodimer partner) and FXR are the link between BAs and TG metabolism. BAs are also ligands for FXR and G-protein-coupled receptors, such as TGR5. FXR activation by BAs suppresses the expression of MTP, transcription factor sterol regulatory element binding protein (SREBP)-1c and other lipogenic genes. LXRs stimulate lipogenesis whereas FXRs inhibit the metabolic process. Synthesis of BAs from cholesterol occurs either via the classical pathway (7α-hydroxylation of cholesterol; CYP7A1) or via the alternate pathway (CYP39A1 or CYP7B1). BAs induce FXR, which inhibits CYP7A1 transcription by activation of SHP and inhibition of HNF4α transactivation. Bile composition (supersaturation with cholesterol), gallbladder dysmotility, inflammation, hypersecretion of mucin gel in the gallbladder and slow large intestinal motility and increased intestinal cholesterol absorption may contribute to the pathogenesis of cholesterol gallstones. In HTG patients supersaturated bile may be related to the presence of obesity rather than to HTG itself. Contraction and relaxation of the gallbladder are regulated by neuronal, hormonal and paracrine factors. Postprandial gallbladder emptying is regulated by cholecystokinin (CCK). Poor postprandial gallbladder contraction may be due to the magnitude of the CCK response and to the amount of CCK receptors in the gallbladder smooth muscle cells. In the fasting state gallbladder motility is associated with the intestinal migrating motor complex (MMC) activity and with elevated plasma motilin levels. Fibroblast growth factor (FGF19), produced on arrival of bile acids in the ileum, is also important for gallbladder motility. Gallbladder motility is impaired in HTG patients compared to BMI matched controls. There is evidence that the gallbladder in HTG is less sensitive to CCK and that this sensitivity improves after reversal of high serum TG levels by use of TG lowering agents. In hypertriglyceridemia TG lowering therapy (fibrates or fish-oil) is essential to prevent cardiovascular disease and pancreatitis. Fibrates, however, also increase the risk for cholelithiasis by increasing biliary cholesterol saturation and by reduction of bile acid synthesis. On the other hand fish-oil decreases biliary cholesterol saturation. Fish-oil may increase bile acid synthesis by activation of 7alpha-hydroxylase and may inhibit VLDL production and secretion through activation of nuclear factors and increased apoB degradation. In HTG patients, gallbladder motility improves during bezafibrate as well as during fish-oil therapy. The question remains whether improvement of gallbladder motility and increased lithogenicity of bile by bezafibrate therapy counteract each other or still result in gallstone formation in HTG patients.

Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers.

Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation may be beneficial in the treatment of several psychiatric disorders, including depression. A small number of studies have suggested that there may also be cognitive and mood effects in healthy samples. The purpose of the present study was to investigate the effects of n-3 PUFA on depression-relevant cognitive functioning in healthy individuals. Fifty-four healthy university students were randomized to receive either n-3 PUFA supplements or placebo for 4 weeks in a double-blind design. The test battery included measures of cognitive reactivity, attention, response inhibition, facial emotion recognition, memory and risky decision-making. Results showed few effects of n-3 PUFAs on cognition and mood states. The n-3 PUFA group made fewer risk-averse decisions than the placebo group. This difference appeared only in non-normative trials of the decision-making test, and was not accompanied by increased impulsiveness. N-3 PUFAs improved scores on the control/perfectionism scale of the cognitive reactivity measure. No effects were found on the other cognitive tasks and no consistent effects on mood were observed. The present findings indicate that n-3 PUFA supplementation may have a selective effect on risky decision making in healthy volunteers, which is unrelated to impulsiveness.

Papillary thyroid carcinoma in a patient with sarcoidosis treated with minocycline.

Long-term treatment with minocycline is occasionally associated with the development of black thyroid syndrome in which thyroid cancer is frequently found. Here, we report a patient with cutaneous, pulmonary and thyroid sarcoidosis who developed papillary thyroid carcinoma in the presence of a black thyroid syndrome after being treated with minocycline for 2.5 years.

Modulating effect of the A-278C promoter polymorphism in the cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals.

The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7alpha-hydroxylase (CYP7A1). An A to C substitution 278 bp upstream in the promoter of the CYP7A1 gene was found to be associated with variations in serum lipid levels in normolipidaemic populations. In the present study, we investigated the involvement of this polymorphism in four different lipid disorders: hypertriglyceridaemia (HTG), combined hyperlipidaemia (CH), familial dysbetalipoproteinaemia (FD) and familial hypercholesterolaemia (FH). In a normolipidaemic male population, homozygous for the apoE3 isoform, an association was found between the AA genotype and higher levels of serum triglycerides (AA: +34%, P = 0.036). In HTG patients, the AA genotype was associated with significantly higher concentrations of total cholesterol (+23%, P = 0.005). There was a tendency towards increased levels of serum triglycerides (+39%, P = 0.06), VLDL-triglycerides (+48%, P = 0.053) and VLDL-cholesterol (+35%, P = 0.059). No significant associations were found between serum lipid levels and the CYP7A1 polymorphism in patients with CH, FD and FH. Our results show that the A-278C polymorphism in the CYP7A1 gene has an effect on triglyceride levels in normolipidaemic males and on cholesterol levels in patients with hypertriglyceridaemia..

Cardiovascular disease and mortality in statin-treated patients with familial hypercholesterolemia.

Patients with familial hypercholesterolemia (FH) are at an increased risk of premature cardiovascular disease (CVD). The benefits of statin therapy are not well known since no placebo controlled studies have been performed in these patients. The aim of this study was to determine the CVD event and mortality risk in statin-treated patients with FH. A total of 345 FH patients were followed prospectively for 8 years. Mortality from CVD was compared to that of the general population. The absolute risk of CVD in patients without a previous history of CVD was 3% per year for men and 1.6% for women. Mortality from CVD in patients without a previous history was 1.4-fold (95% CI = 0.6-3.3) increased and ischaemic heart disease (IHD) mortality was 2.6-fold (95% CI = 1.1-6.3) higher compared to the general population. This mortality risk was highest in patients aged 40-59 years. Female FH patients had no increased CVD or IHD mortality risk. Over a period of 8 years the event risk of patients with a history of CVD was almost 30% per year under age 40 years and 15% in patients aged 60 years and over. When compared to the general population, mortality from other causes than CVD was lower for patients with FH, the relative risks not reaching statistical significance. The relative risk of mortality from all causes was 1.5 (P < 0.05) for men and 1.0 for women. In conclusion, male patients with FH, treated from middle-age with statins remain at an increased risk of developing CVD.

Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects.

In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is familial dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.

Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size.

A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.

[From gene to disease; apolipoprotein E2 and familial dysbetalipoproteinemia]. / Van gen naar ziekte; apolipoproteïne E2 en familiaire dysbètalipoproteïnemie.

Familial dysbetalipoproteinaemia is an autosomal recessive, hereditary disorder of lipid metabolism caused by mutations in the apolipoprotein E gene. Homozygosity for apoE2 (1 in 170 persons) causes type III hyperlipoproteinaemia in less than 20% of the adult E2 homozygotes. The patients may present with typical skin lesions and have elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional genetic and environmental factors are necessary for the expression of this hyperlipoproteinaemia. Hyperinsulinaemia and defects in genes involved in the hydrolysis of triglycerides are associated with this disorder.

Gall bladder dysmotility: a risk factor for gall stone formation in hypertriglyceridaemia and reversal on triglyceride lowering therapy by bezafibrate and fish oil.

BACKGROUND AND AIM: The aim of this study was to unravel the mechanisms responsible for the increased risk of gall stone disease in hypertriglyceridaemia (HTG) and to compare the effects of triglyceride lowering therapy by bezafibrate and fish oil on determinants of cholelithiasis (biliary lipid composition and gall bladder motility) in HTG patients. PATIENTS AND METHODS: Gall bladder motility (ultrasonography) was studied postprandially and during infusion of cholecystokinin (CCK). Determinants of cholelithiasis and serum lipids were compared between nine HTG patients and 10 age, sex, and body mass index matched normolipidaemic controls. The effects of bezafibrate and fish oil in HTG patients were studied in a randomised cross over trial. RESULTS: HTG patients showed 14-fold higher serum triglyceride (TG) levels than controls. Biliary lipid composition, fasting gall bladder volumes, and CCK levels did not differ between HTG patients and controls. Gall bladder emptying was reduced in HTG patients compared with controls during CCK infusion (-22%) as well as in response to a meal (-37%; both p<0.001). Postprandial CCK levels were significantly higher in HTG patients. Both bezafibrate and fish oil reduced serum TG levels (-68% and -51% v baseline, respectively; both p<0.01). Fasting CCK levels were not affected whereas CCK induced gall bladder emptying increased during bezafibrate (+29%; p<0.001) and tended to increase on fish oil therapy (+13%; p=0.07). Postprandial gall bladder motility improved on bezafibrate and fish oil (+47 and +25% v baseline, respectively; both p<0.02) at least partly due to increased gall bladder sensitivity to CCK (both p<0.05 v baseline). Bezafibrate but not fish oil increased the molar ratio of cholesterol to bile acids (+40%; p

Long term efficacy and safety of atorvastatin in the treatment of severe type III and combined dyslipidaemia.

BACKGROUND: Fibric acid derivatives and HMG-CoA reductase inhibitors are effective in combination for treating patients with familial dysbetalipoproteinaemia and severe combined dyslipidaemia, but combination therapy affects compliance and increases the risk of side effects. AIM: To evaluate the efficacy and safety of monotherapy with atorvastatin, an HMG-CoA reductase inhibitor with superior efficacy in lowering low density lipoprotein cholesterol and triglyceride concentrations, in patients with dysbetalipoproteinaemia and severe combined dyslipidaemia. METHODS: Atorvastatin was tested as single drug treatment in 36 patients with familial dysbetalipoproteinaemia and 23 patients with severe combined dyslipidaemia. RESULTS: After 40 weeks of 40 mg atorvastatin treatment decreases in total cholesterol, triglycerides, and apolipoprotein B of 40%, 43%, and 41%, respectively, were observed in the combined dyslipidaemia group, and of 46%, 40%, and 43% in the dysbetalipoproteinaemic patients. Target concentrations of total cholesterol (< 5 mmol/l) were reached by 63% of the patients, and target concentrations of triglycerides (< 3.0 mmol/l) by 66%. Treatment with atorvastatin was well tolerated and no serious side effects were reported. CONCLUSIONS: Atorvastatin is very effective as monotherapy in the treatment of familial dysbetalipoproteinaemia and severe combined dyslipidaemia.

The effect of tibolone on the lipoprotein profile of postmenopausal women with type III hyperlipoproteinemia.

OBJECTIVE: To investigate the short-term effect of treatment with tibolone on plasma lipid and lipoprotein levels in postmenopausal women with type III hyperlipoproteinemia (HLP). DESIGN AND INTERVENTION: Patients were randomized to receive, in a double-blind cross-over fashion, a fixed dose of tibolone, 2.5 mg once daily or placebo for 8 weeks. The two treatment periods were separated by a wash-out period of 6 weeks. At each visit body weight and blood pressure were determined. Before and after each treatment period, fasting venous blood samples were obtained from the patients for biochemical measurements. SETTING: The Leiden University Medical Center. SUBJECTS: Postmenopausal women with type III HLP (aged < or = 65 years) were recruited from the Lipid Clinics of the Leiden University Medical Center, the Amsterdam Medical Center, the Utrecht Medical Center and the University Hospital Rotterdam. Five out of 25 women with type III HLP were eligible to be included in the study. Four of the five included patients completed the study according to the protocol. One patient was excluded from blinded therapy because total cholesterol levels increased above 20 mmol L(-1). MAIN OUTCOME MEASURES: A significant reduction of plasma triglyceride, total cholesterol, VLDL cholesterol and VLDL triglyceride levels. RESULTS: Plasma triglyceride and total cholesterol levels decreased from 6.82 +/- 3.58 to 2.45 +/- 1.36 mmol L(-1) and from 13.53 +/- 3.64 to 6.61 +/- 2.03 mmol L(-1), respectively (both P < 0.05). The body mass index remained unchanged. The glycated haemoglobin percentage decreased significantly from 5.8 to 5.3%. Treatment with tibolone resulted in a profound reduction in plasma apolipoprotein E, VLDL cholesterol and VLDL triglyceride levels (mean reductions of 66, 77 and 70%, respectively, P < 0.05). CONCLUSIONS: Tibolone is a valuable adjuvant to current therapy in postmenopausal women with type III HLP.

Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia.

OBJECTIVES: To infer the relative impact of elevated triglyceride levels and insulin resistance on endothelial dysfunction in patients with chronic hypertriglyceridemia (HTG). METHODS: Endothelial function was studied in 11 HTG patients and 16 normolipidemic controls. Cumulative-dose infusions of 5-hydroxytryptamine (5HT) and sodium nitroprusside were infused locally into the brachial artery to study endothelium-dependent and endothelium-independent vasodilation, respectively. Data of the HTG patients were dichotomized around the median of insulin resistance, calculated as HOMA-index, forming HTG groups with mild (HTG-MIR) and severe insulin resistance (HTG-SIR). RESULTS: HTG patients had higher triglyceride levels and smaller LDL particle size than controls (both P< or =0.001), whereas these parameters did not differ between both HTG groups. Insulin resistance was higher in both HTG groups than in controls (11.1 (7.0-14.5) and 4.9 (4.0-6.7) vs. 2.4 (4.9-5.2), respectively, both P<0.001). Similarly, free fatty acid levels, another indicator of insulin resistance, were highest in the HTG-SIR group, followed by those in the HTG-MIR and control group (0.7 (0.6-0.8), 0.5 (0.4-0.6) and 0.4 (0.3-0.4) mmol/l, respectively, all P<0.05). Endothelial-dependent vasodilation was similar in HTG-MIR and controls. In contrast, the response to 5HT was attenuated in the HTG-SIR group compared to controls (low and high dose by, respectively, -60 and -44%, both P<0.01), and tended to be lower than in the HTG-MIR group (-43%, P=0.068 and -41%, P=0.100, respectively). Endothelium-independent vasodilation did not differ between the three groups. CONCLUSION: These findings indicate that chronic hypertriglyceridemia per se is not associated with endothelial dysfunction. In contrast, the presence of insulin resistance, characterized by hyperinsulinemia and FFA elevation, contributes to the induction of endothelial dysfunction in chronic HTG.

Failure to induce delayed-type hipersensivity to Mycobacterium leprae in long-term treated lepromatous leprosy patients

Lepromatous leprosy (LL) patients whose bacillary load has decreased to almost undetectable levels by long-term chemotherapy failed to develop delayed-type hypersensitivity (DTH) to Mycobacterium leprae antigen following immunization with killed armadillo-derived m. leprae. When these LL patients were immunized with killed M. leprae in a mixture with live BCG, only DTH to purified protein derivative (PPD) was induced. These results are further evidence that immunological unresponsiveness to the leprosy antigen of patients with lepromatous leprosy is antigen-specific and non-reversible.